July 24, 2016
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OraVerse

Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Cardiovascular Events

Myocardial infarction, cerebrovascular spasm, and cerebrovascular occlusion have been reported to occur following the parenteral administration of phentolamine. These events usually occurred in association with marked hypotensive episodes producing shock-like states. Tachycardia and cardiac arrhythmias may occur with the use of phentolamine or other alpha-adrenergic blocking agents. Although such effects are uncommon after administration of OraVerse, clinicians should be alert to the signs and symptoms of these events, particularly in patients with a prior history of cardiovascular disease.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

Carcinogenic studies with OraVerse have not been conducted.

Mutagenesis

Phentolamine was not mutagenic in the in-vitro bacterial reverse mutation (Ames) assay. In the in-vitro chromosomal aberration study in Chinese hamster ovary cells, numerical aberrations were slightly increased after a 4-hour exposure to phentolamine without metabolic activation and structural aberrations were slightly increased after a 4-hour exposure to phentolamine with metabolic activation only at the highest concentrations tested, but neither numerical nor structural aberrations were increased after a 20-hour exposure without metabolic activation. Phentolamine was not clastogenic in two in-vivo mouse micronucleus assays.

Impairment Of Fertility

The effect of phentolamine on female fertility has not been studied. Male rats treated with oral phentolamine for nine weeks (four weeks prior to mating, 3 weeks during the mating period and 2 weeks after mating) were mated with untreated females. At doses up to 143-times human therapeutic exposure levels at the Cmax, no adverse effects on male fertility parameters or on reproductive parameters in the untreated females mated with the treated males were observed.

Use In Specific Populations

Pregnancy

Pregnancy Category C.

Risk summary

There are no available data with OraVerse in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. In animal toxicology studies, phentolamine administered orally to pregnant mice and rats during the period of organogenesis resulted in skeletal immaturity and decreased growth in the offspring at doses at least 24-times the recommended dose. Additionally, a lower rate of implantation was seen in pregnant rats treated with phentolamine at least 60-times the recommended dose. No malformations or embryofetal deaths were observed in the offspring of pregnant mice, rats, and rabbits administered phentolamine during the period of organogenesis at doses 24-, 60-, and 20-times, respectively, the recommended dose [see Data].

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Animal Data

Oral administration of phentolamine to pregnant rats and mice at doses at least 24-times the recommended dose (based on a mg/m² comparison with a 60 kg human) resulted in slightly decreased growth and slight skeletal immaturity of the fetuses. Immaturity was manifested by increased incidence of incomplete or unossified calcanei and phalangeal nuclei of the hind limb and of incompletely ossified sternebrae. At oral phentolamine doses at least 60-times the recommended dose (based on a mg/m² comparison with a 60 kg human),a slightly lower rate of implantation was found in the rat. Phentolamine did not affect embryonic or fetal development in the rabbit at oral doses at least 20-times the recommended dose (based on a mg/m² comparison with a 60 kg human). No malformations or embryofetal deaths were observed in the rat, mouse or rabbit studies.

Lactation

Risk Summary

There is no information regarding the presence of phentolamine in human milk, the effects on the breastfed infant or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for OraVerse and any potential adverse effects on the breastfed infant from OraVerse, or from the underlying maternal condition.

Pediatric Use

The safety and efficacy of OraVerse has not been established in patients younger than 3 years.

The safety and effectiveness of OraVerse in pediatric patients ages 3 years and older is supported by evidence from adequate and well-controlled studies of OraVerse in adults, with additional adequate and well-controlled studies of OraVerse in pediatric patients ages 12-17 years old [Studies 1 (mandibular procedures) and 2 (maxillary procedures)], ages 6-11 years old [Study 3 (mandibular and maxillary procedures)], and another study in patients ages 2-5 years [Study 4]. Study 4 assessed safety and effectiveness in patients 4 to 5 years, but was not designed to demonstrate efficacy. Use in patients 3 to < 4 years is supported by similar pharmacokinetics and safety in these patients compared with older pediatric patients (see CLINICAL PHARMACOLOGY]. Use of OraVerse in this age group (3 to < 4 years) is also supported by the similarity in the exposure response of OraVerse for pediatric and adult patients, and the adequacy of the safety database for patients age ≥ 3. The safety database for patients age < 3 is limited, and therefore, use in patients age < 3 is not recommended. Dosages in pediatric patients may need to be limited based on body weight. [see DOSAGE AND ADMINISTRATION]

Geriatric Use

Of the total number of patients in clinical studies of OraVerse, 55 were 65 and over, while 21 were 75 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elder and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

This monograph has been modified to include the generic and brand name in many instances.

Last reviewed on RxList: 6/21/2016

Warnings
Precautions

Report Problems to the Food and Drug Administration

 

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.


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